Peripheral nerve sheath tumors are a prevalent feature of neurofibromatosis type 1 (NF1) and Schwann cells which express relatively high amounts of neurofibromin, appear to be particularly vulnerable to NF1 gene defects. Schwann cell tumors, including those in NF1, exhibit graded malignancy and several grades of tumors may afflict a single NF1 patient. Individual Schwann cell tumors may show loss of growth control, heightened invasive properties or metastasis. Particular neoplastic traits are categorically observed in NF1 Schwann cell tumors whereby benign Schwann cell tumors such as cutaneous neurofibroma exhibit slow extraneural growth, plexiform neurofibroma retain intraneural association but may become massive, and neurofibrosarcoma are both highly invasive and proliferative. Neoplastic traits by cultured Schwann cells often correlate with expression of matrix metalloproteinases (MMPs). The present proposal will examine neurofibromin and MMP expression and will characterize neoplastic traits exhibited by a variety of normal, tumor-derived, and NF1-mutant Schwann cells. Neoplastic traits include absence of negative growth control, growth in soft agarose, heightened invasion of synthetic and natural extracellular matrices, elevated levels of certain MMPs, and tumor formation in vivo. Additionally, it will be determined if neurofibromin protein levels are systematically altered in cultures of NF1 and non-NF1 Schwann cell tumors. Experiments are designed to test the following hypotheses: a) neoplastic Schwann cells exhibit altered negative growth involving MMP-3; b) neoplastic Schwann cells have altered invasion potentials which correspond to expression levels of MMP-1, MMP-2, and/or MMP-9; c) neurofibromin interacts directly with Schwann cell tumorigenicity; and d) the severity of neurofibromin-deficiency correlates with loss of growth control, heightened invasion potential and malignancy. These studies are designed to test the general hypothesis that Schwann cells derived from tumors with different grades of malignancy also exhibit categorically different neoplastic traits in vitro. Also, experiments will determine if neurofibromin governs individual aspects of Schwann cell neoplasia. In order to more directly implicate a role for neurofibromin in Schwann cell neoplasia, we propose the use of NF1 mRNA-and gene targeting strategies.